Receptor for advanced glycation end products is targeted by FBXO10 for ubiquitination and degradation

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
John EvankovichRama K Mallampalli

Abstract

The receptor for advanced glycation end products (RAGE) is a highly expressed cell membrane receptor serving to anchor lung epithelia to matrix components, and it also amplifies inflammatory signaling during acute lung injury. However, mechanisms that regulate its protein concentrations in cells remain largely unknown. Here we show that RAGE exhibits an extended life span in lung epithelia (t½ 6 h), is monoubiquitinated at K374, and is degraded in lysosomes. The RAGE ligand ODN2006, a synthetic oligodeoxynucleotide resembling pathogenic hypomethylated CpG DNA, promotes rapid lysosomal RAGE degradation through activation of protein kinase Cζ (PKCζ), which phosphorylates RAGE. PKCζ overexpression enhances RAGE degradation, while PKCζ knockdown stabilizes RAGE protein levels and prevents ODN2006-mediated degradation. We identify that RAGE is targeted by the ubiquitin E3 ligase subunit F-box protein O10 (FBXO10), which associates with RAGE to mediate its ubiquitination and degradation. FBXO10 depletion in cells stabilizes RAGE and is required for ODN2006-mediated degradation. These data suggest that modulation of regulators involved in ubiquitin-mediated disposal of RAGE might serve as unique molecular inputs directing RAGE cellula...Continue Reading

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Citations

Aug 16, 2019·American Journal of Respiratory Cell and Molecular Biology·Laxman Ghimire, Samithamby Jeyaseelan
Mar 4, 2020·International Journal of Molecular Medicine·Yuanzhi LiWeiliang Du
Mar 12, 2020·Frontiers in Cell and Developmental Biology·Stephanie D BurrJames A Stewart Jr
Aug 7, 2019·American Journal of Respiratory Cell and Molecular Biology·John EvankovichBill B Chen
Jan 29, 2020·JCI Insight·Yao TongBill B Chen
Apr 4, 2021·International Journal of Molecular Sciences·Galina M ViryasovaGalina F Sud'ina
Nov 2, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Daniel PrantnerStefanie N Vogel
Jul 11, 2021·Nature Communications·Zhongyuan BaoJing Ji
Aug 10, 2021·Critical Reviews in Food Science and Nutrition·Olívia G L CoelhoRita de Cássia G Alfenas

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